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HIV vaccine feat leaves more questions than answers

A combination of vaccines is found to provide modest protection against infection. Now scientists have to find out how that happened.

By Karen Kaplan and Thomas H. Maugh II

September 25, 2009

Only hours after HIV vaccine researchers announced the achievement of a milestone that has eluded them for a quarter of a century, they began plotting their next steps -- and coming to grips with a sobering reality. Their ultimate goal, halting the spread of AIDS, remains far in the future.

A Thai and American team had announced early Thursday in Bangkok that they had found a combination of vaccines that provided modest protection against infection with HIV, offering the first proof of principle that the deadly disease could be tamed by teaching the immune system to recognize the virus and defeat it.

But by Thursday afternoon, the initial wave of euphoria had given way to the recognition that many vexing questions will have to be answered before researchers can produce a vaccine that will reliably shield people from HIV.

For starters, it could take years to unravel the biological mechanisms that produced the apparent 31% reduction in infections among those given the vaccine regimen.

Researchers have never before observed antibodies or other molecules in the blood that could block an infection of HIV, the virus that causes AIDS. Now they will try to figure out whether this combination of vaccines stimulated new molecules, or provoked an unusual blend of ones previously observed.

Experts predicted that it would require two to three years of research to better understand how the vaccine worked, and an additional five to 10 years to produce a vaccine that was ready to test in people.

Some researchers even wondered whether the apparent reduction in infections was simply a statistical fluke resulting from the small number of HIV cases observed in the trial.

The abundance of unanswered questions hasn't sapped the enthusiasm of many HIV researchers. After 26 years of seemingly futile research on vaccines, they have finally made some progress on demonstrating the feasibility of an HIV vaccine, said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which largely funded the $120-million study.

"This is the first positive signal -- modest though it may be -- that we have ever gotten with any vaccine that we have ever tested in humans," Fauci said. But "is it a vaccine that is ready for prime time? No."

The Thai trial, which began in 2003, had been disparaged by many critics as a waste of time and money because its two vaccines had produced no benefit in individual trials. But a few researchers speculated that using them together -- with one vaccine priming the immune system and the second boosting that response -- would be more effective.

The primer in this combo is Alvac, made by Sanofi Pasteur, which uses a defanged canarypox virus to carry three synthetic HIV genes into the body. The boost comes from Aidsvax, originally made by VaxGen Inc. and now owned by the nonprofit group Global Solutions for Infectious Diseases. It contains a genetically engineered version of a protein from the HIV surface.

The study, led by Dr. Supachai Rerks-Ngarm of the Thai Ministry of Public Health's Department of Disease Control, involved more than 16,000 volunteers in Thailand, all from the general population rather than from a pool of high-risk homosexuals and intravenous drug users used in past studies. Half received four priming doses of Alvac and two boost doses of Aidsvax over a six-month period; the other half received placebo shots.

After three years of follow-up, new HIV infections were observed in 74 of the 8,198 people who received the placebo, but in only 51 of the 8,197 given the vaccine, a statistically significant 31% reduction.

To the researchers' disappointment, however, the vaccine did not reduce levels of HIV activity in those who became infected after being vaccinated.

The trial was carried out in Thailand because the initial research was conducted there and the vaccine was based on the version of HIV that circulates in that country.

Full details of the study will be released next month at a conference in Paris, and researchers are eagerly awaiting them.

Dr. Salim S. Abdool Karim, an epidemiologist at Columbia University in New York and director of the Centre for the AIDS Programme of Research in South Africa in Durban, said he was particularly eager to know whether people who got vaccinated and stayed healthy had a bigger response from the white blood cells known as cellular T lymphocytes.

"A whole range of vaccines were developed on the hypothesis that they generated sufficient [cellular T lymphocyte] responses to either prevent infection or impact viral load," he said. "We've never been able to test that hypothesis because no vaccine has worked until now."

And if it is not the lymphocytes, then "what kind of compounds were the cells making when you inoculate them with the vaccine?" asked Dr. Spyros Kalams, an HIV immunology researcher at Vanderbilt University in Nashville and director of the HIV Vaccine Trials Program there. "Was it a compound that can kill infected cells? Does it make proteins that stop the virus from replicating?"

Researchers now will begin the painstaking work of comparing the blood of those who were vaccinated and resisted infection and those who did not. Then they will look for molecules that are more abundant in the healthy people, Fauci said.

Once researchers identify these so-called correlates of immunity, they can begin to look for ways to prompt the body to make them -- the key to producing an effective vaccine.

The Thai results are "an opening of a door to answer some very important questions," he said.

But several scientists cautioned that there was no guarantee the Thai blood samples would reveal the biological secrets of HIV immunity.

Surely some of the people who resisted HIV infection were protected by the vaccine, but not all, said Dr. Otto Yang, an immunologist at UCLA's David Geffen School of Medicine.

Yang also expressed doubt that a combination of vaccines made the difference in those who benefited. He and others noted that this was the first large study to focus on a low-risk population. Perhaps transmitting the virus through heterosexual sex instead of directly into the bloodstream on an intravenous needle gives the immune system a better chance of fighting off infection.

Although it is also unclear whether these particular vaccines could be used elsewhere in the world, scientists said that if they could figure out what made this combination work, they could localize the approach to other regions. The dominant HIV strains vary from region to region.

At least 33 million people worldwide are infected with HIV and 25 million have died, the World Health Organization said. An estimated 7,500 are infected each day, accentuating the need for a vaccine.

There have been three previous vaccine trials in humans. Aidsvax had previously failed in two large trials halted in 2003; both showed no benefit to recipients. Another trial by Merck & Co. of a different vaccine was halted prematurely in 2007 when researchers found that the vaccine might increase the risk of contracting the virus.